Tryptophan is metabolized in mammals via the kynurenine pathway to yield three neuroactive substances, 3-hydroxykynurenine, kynurenic acid and quinolinic acid. Kynurenic acid has neuroprotective activities in vivo while 3-hydroxykynurenine and quinolinic acid are neurotoxic. Studies have shown that 3-hydroxykynurenine and quinolinic acid are causative or contribute to delayed neurological damages and are associated with a variety of human diseases including neurodegenerative disorders and psychiatric diseases. Pharmacological intervention aimed at blocking 3-hydroxykynurenine and quinolinic acid synthesis and/or increasing kynurenic acid formation have been attempted in treatment of neurological diseases and their peripheral indications, such as diabetes.
Kynurenine-3-monooxygenase (KMO) is an enzyme in the tryptophan degradation pathway that catalyzes the conversion of kynurenine into 3-hydroxykynurenine which is a precursor of the neurotoxin quinolinic acid. Therefore, compounds which act as inhibitors of KMO are of particular interest since they block the metabolism toward quinolinic acid and at the same time, increase the formation of neuroprotective metabolite kynurenic acid.
Inhibitors of KMO have been known in the art. For example, U.S. Pat. No. 5,877,193 describes N-(4-arylthiazol-2-yl)-sulfonamide derivatives for treating neurodegenerative disorders resulting from an activation of the immune system.
There remains a need for compounds that are effective inhibitors of KMO and can be used in treating neurodegenerative disorders. Compounds that inhibit KMO and can thus be used to treat and prevent KMO-associated disorders including neurodegenerative disorders are provided herein.